1. Field of the Invention
The present invention relates to a novel thiazetoquinoline-3-carboxylic acid derivative and a pharmacologically acceptable salt thereof which has an excellent antibacterial activity and is useful as a synthetic antibacterial agent, and to the method for preparation thereof.
The present invention also relates to a pharmaceutical composition comprising the effective amount of the same which is useful for the treatment of an infectious disease.
More particularly, the present invention relates to a thiazetoquinoline-3-carboxylic acid derivative represented by the following general formula (I): ##STR2## wherein R.sub.1 is a hydrogen atom or a lower alkyl group; R.sub.2 is a fluorine atom or a chlorine atom; R.sub.3 is a hydrogen atom, a lower alkyl group, a lower alkanoyl group, a halogenated lower alkanoyl, or alkoxycarbonyl group; and R.sub.4 is a hydrogen atom or a lower alkyl group. The present invention also relates to a pharmacologically acceptable salt of compounds of general formula (I), a process for preparing the same, and a pharmaceutical composition comprising the same together with a pharmaceutically acceptable carrier or coating.
2. Description of the Prior Art
Since the development of nalidixic acid, pyridonecarboxylic acids antibacterials have become the chief, most widely used antibacterial chemotherapeutants for the clinical treatment of an infectious diseases such as urinary tract infection, intestinal infection and cholangia infection.
Recently, norfloxacin (The Merck Index, 11th Edition, 6617), ofloxacin (The Merck Index, 11th Edition, 6688), and ciprofloxacin (The Merck Index, 11th Edition, 2315) represented by the following formula (II): ##STR3## were synthesized successively and have been found to have excellent antibacterial activities and a wide antibacterial spectra compared with known synthetic antibacterials. These compounds have been developed as antibacterial agents on the market for the clinical treatment of prostatitis, or otolaryngologic, internal, ophthalmologic, and dental infections as well as the above-mentioned infectious diseases.
Japanese Unexamined Patent Publication No. 107990/1988 discloses 6-fluoro-1-methyl-4-oxo-7-(1-piperazinyl)-1H,4H-[1,3]thiazeto[3,2-a]quinol ine-3-carboxylic acid represented by the following formula (III): ##STR4## Japanese Unexamined Patent Publication No. 230584/1989 discloses 6,8-difluoro-1-methyl-4-oxo-7-(1-piperazinyl)-1H,4H-[1,3]thiazeto[3,2-a]qu inoline-3-carboxylic acid represented by the following formula (IV): ##STR5## Japanese Unexamined Patent Publication No. 107990/1988 discloses 7-(3-amino-1-pyrrolidinyl)-6-fluoro-1-methyl-4-oxo-1H,4H-[1,3]thiazeto[3,2 -a]quinoline-3-carboxylic acid represented by the following formula (V): ##STR6## Japanese Unexamined Patent Publication No. 230584/1989 discloses 7-(3-amino-1-pyrrolidinyl)-6,8-difluoro-4-oxo-1H,4H-[1,3]thiazeto[3,2-a]qu inoline-3-carboxylic acid represented by the following formula (VI): ##STR7## However, none of the above documents discloses a thiazetoquinoline compound having substituents of a methyl group, an aminopyrrolidinyl group, and a halogen atom in the 1, 7, and 8 positions of the thiazetoquinoline ring, respectively. Further, the utility of an optically active aminopyrrolidinyl substituent is not taught by any prior art.
Pyridonecarboxylic acid antibacterials have been remarkably improved since the discovery of norfloxacin, and have been found to be useful for the clinical treatment of various kinds of infections diseases including urinary tract infection. The mode of antibacterial action of the pyridonecarboxylic acid antibacterials is believed to be an inhibitory action against DNA gyrase which is classified as a DNA topoisomerase. It is also believed that a bacterial resistance against a pyridonecarboxylic acid is not transmitted to other bacteria via plasmid DNAs, unlike other antibiotics.
Clinically, however, low-sensitive strains against the pyridonecarboxylic acids have found to be increasing, and the developed antibacterials has become ineffective for the treatment of intractable diseases such as for example a chronic infection caused by Pseudomonas aeruginosa or Gram-positive bacterial infections. Furthermore, some pyridonecarboxylic acid antibacterial agents have been revealed to cause convulsions when used in combination with certain anti-inflammatory agents.
Therefore, the above-mentioned, presently available antibacterials are insufficient from a clinical point of view. Much improvement has been longed for with respect to (1) antibacterial activities against clinically isolated resistant bacteria and (2) safety of administration, e.g., eliminating possible convulsions caused by administration with an anti-inflammatory agent.